Evaluation of the Antiviral Activity of Sephin1 Treatment and Its Consequences on eIF2α Phosphorylation in Response to Viral Infections

Fusade-Boyer, Maxime; Dupré, Gabriel; Bessière, Pierre; Khiar, Samira; Beck, Cécile; Lecollinet, Sylvie; Rameix‐Welti, Marie‐Anne; Éléouët, Jean-François; Tangy, Frédéric; Lajoie, Barbora; Bertagnoli, Stéphane; Vidalain, Pierre‐Olivier; Gallardo, Franck; Volmer, Romain

doi:10.3389/fimmu.2019.00134

Cited by 16 publications

(12 citation statements)

References 57 publications

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“…The activation of the IFN-I response requires PACT, which interacts with RNA polymerase, and nonstructural proteins NS1 and NS2 of influenza A virus 44 . Influenza virus replication depends on the interaction of virus-encoded proteins with host factors, which regulate pivotal aspects of cell survival; virus recognition, replication and pathogenicity; and host defence 45,46 . It has been reported that PACT is a crucial antiviral host factor that mediates the activation of the dsRNA-dependent kinase PKR, and stimulates substantial RIG-I activation to induce IFN-I production 47 .…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication

Guo

Bao

et al. 2020

Sci Rep

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Epidemic and pandemic influenza A virus (IAV) poses a significant threat to human populations worldwide. Iridoid glycosides are principal bioactive components from the Gardenia jasminoides J. Ellis fruit that exhibit antiviral activity against several strains of IAV. In the present study, we evaluated the protective effect of Fructus Gardeniae iridoid glycoside extracts (IGEs) against IAV by cytopathogenic effect(CPE), MTT and a plaque formation assay in vitro and examined the reduction in the pulmonary index (PI), restoration of body weight, reduction in mortality and increases in survival time in vivo.As a host factor, PACT provides protection against the pathogenic influenza A virus by interacting with IAV polymerase and activating the IFN-I response. To verify the whether IGEs suppress IAV replication in a PACT-dependent manner, IAV RNA replication, expression of PACT and the phosphorylation of eIF2α in A549 cells were detected; the levels of IFNβ, PACT and PKR in mouse lung tissues were determined; and the activity of IAV polymerase was evaluated in PACT-compromised cells. The results indicated that IGEs sufficiently alleviated cell damage and suppressed IAV replication in vitro, protecting mice from IAV-induced injury and lethal IAV infection. These anti-IAV effects might be related to disrupted interplay between IVA polymerase and PACT and/or prevention of a PACT-dependent overactivated IFN-I antiviral response. Taken together, our findings reveal a new facet of the mechanisms by which IGEs fight the influenza A virus in a PACT-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication

Guo

Bao

et al. 2020

Sci Rep

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“…eIF2α, a balance point between cellular resistance to viruses and virus-induced apoptosis or autophagy, is essential for cell survival. Anne Bertolotti et al found that the phosphatase regulatory subunit PPP1R15A (R15A) inhibitor Sephin1 could increase the eIF2α phosphorylation level [161], and studies have shown that Sephin1 has inhibitory effects on some RNA and DNA viruses [162]. In addition, pathologic changes caused by viruses can induce cancerous changes in cells, such as HCC development in patients with HCV infection [163,164].…”

Section: Resultsmentioning

confidence: 99%

The role of host eIF2α in viral infection

Liu¹,

Wang²,

Cheng³

et al. 2020

Virol J

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Background eIF2α is a regulatory node that controls protein synthesis initiation by its phosphorylation or dephosphorylation. General control nonderepressible-2 (GCN2), protein kinase R-like endoplasmic reticulum kinase (PERK), double-stranded RNA (dsRNA)-dependent protein kinase (PKR) and heme-regulated inhibitor (HRI) are four kinases that regulate eIF2α phosphorylation. Main body In the viral infection process, dsRNA or viral proteins produced by viral proliferation activate different eIF2α kinases, resulting in eIF2α phosphorylation, which hinders ternary tRNAMet-GTP-eIF2 complex formation and inhibits host or viral protein synthesis. The stalled messenger ribonucleoprotein (mRNP) complex aggregates under viral infection stress to form stress granules (SGs), which encapsulate viral RNA and transcription- and translation-related proteins, thereby limiting virus proliferation. However, many viruses have evolved a corresponding escape mechanism to synthesize their own proteins in the event of host protein synthesis shutdown and SG formation caused by eIF2α phosphorylation, and viruses can block the cell replication cycle through the PERK-eIF2α pathway, providing a favorable environment for their own replication. Subsequently, viruses can induce host cell autophagy or apoptosis through the eIF2α-ATF4-CHOP pathway. Conclusions This review summarizes the role of eIF2α in viral infection to provide a reference for studying the interactions between viruses and hosts.

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“…eIF2α is essential for translation initiation. Phosphorylation inactivates eIF2α leading to inhibition of translation initiation and reduced protein production, helping the stressed cells to deal with accumulated unfolded proteins. − In turn, the holoenzymes PP1c:PPP1R15A (also called GADD34) and PP1c:PPP1R15B (also called CReP) dephosphorylate eIF2α, reinitiating protein translation. − …”

Section: Protein Phosphatase-1: Targeting Of Holoenzyme Formationmentioning

confidence: 99%

Turn and Face the Strange: A New View on Phosphatases

Köhn

2020

ACS Cent. Sci.

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Phosphorylation as a post-translational modification is critical for cellular homeostasis. Kinases and phosphatases regulate phosphorylation levels by adding or removing, respectively, a phosphate group from proteins or other biomolecules. Imbalances in phosphorylation levels are involved in a multitude of diseases. Phosphatases are often thought of as the black sheep, the strangers, of phosphorylation-mediated signal transduction, particularly when it comes to drug discovery and development. This is due to past difficulties to study them and unsuccessful attempts to target them; however, phosphatases have regained strong attention and are actively pursued now in clinical trials. By giving examples for current hot topics in phosphatase biology and for new approaches to target them, it is illustrated here how and why phosphatases made their comeback, and what is envisioned to come in the future.

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Evaluation of the Antiviral Activity of Sephin1 Treatment and Its Consequences on eIF2α Phosphorylation in Response to Viral Infections

Cited by 16 publications

References 57 publications

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication

Antiviral activity of iridoid glycosides extracted from Fructus Gardeniae against influenza A virus by PACT-dependent suppression of viral RNA replication

The role of host eIF2α in viral infection

Turn and Face the Strange: A New View on Phosphatases

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